Method for preparing particles comprising metal oxide coating and particles with metal oxide coating

ABSTRACT

The invention relates to a process for coating a solid, water-insoluble particulate matter, with a metal oxide comprising: (a) contacting the solid, water-insoluble particulate matter with an ionic additive and an aqueous medium to obtain a dispersion of said particulate matter having positive charges on its surface; (b) subjecting the particulate matter to a coating procedure comprising precipitating a metal oxide salt onto the surface of the particulate matter to form a metal oxide layer thereon to thereby obtain particulate matter coated by a metal oxide coating layer; (c) repeating step (b) at least 4 more times; and (d) aging said coating layer. The invention further relates to particles comprising a particulate matter coated by a metal oxide layer, to a use of the particles for topical administration, and to a method for preventing, reducing, or eliminating pests at a locus, using the particles.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional Application from U.S. patentapplication Ser. No. 12/525,331, filed Oct. 6, 2009, which is a USNational Phase of PCT International Application No. PCT/IL2008/000141,filed Feb. 3, 2008, claiming priority from U.S. Provisional PatentApplication No. 60/898,700, filed Feb. 1, 2007, which are allincorporated in their entirety herein by reference.

FIELD OF THE INVENTION

The present invention generally relates to method for preparation ofparticles comprising metal oxide coating layer and to compositionscomprising particles with metal oxide coating.

BACKGROUND OF THE INVENTION

Metal oxides have been used as encapsulating materials and as matricesfor various applications such as cosmetics, biomaterials, optics, laser,florescence, etc. using a variety of methods.

Shells consisting of hybrid inorganic-organic structures with bulk andsurface properties that are compositionally controlled have beendescribed in Hall, Simon, R., et al., Cocondensation of OrganosilicaHybrid Shells on Nanoparticle, Templates: A Direct Synthetic Route toFunctionalized Core—Shell Colloids, Langmuir, 16:1454-1456, 2000.

The formation of silica shells on core silver particles by a modifiedStober process is reported by Matijevi et al in Journal of Colloid andInterface Science, Volume 221, Issue 1, 1 Jan. 2000, Pages 133-136. Theyalso report on the formation of spherical particles of Cu(II) basiccarbonate coated with amorphous titania by hydrolysis of Ti(IV) butoxidein Colloids and Surfaces A: Physicochemical and Engineering Aspects,Volume 81, 13 Dec. 1993, Pages 153-159. In this report they show how thethickness of the shell could be varied by altering the experimentalconditions. White pigments (whiteners) were prepared by coatingmonodispersed silica particles with titania. The hiding power of thispowder was evaluated as a function of the particle diameter, thethickness of the titania shell, and the calcination temperature.Matijevi et al, Journal of Colloid and Interface Science, Volume 156,Issue 1, 1 Mar. 1993, Pages 56-65.

Colloidal boehmite (A1OOH) rods were used as cores for the preparationof rods with a silica shell as described in van Bruggen, M. P. B.,Preparation and Properties of Colloidal Core—Shell Rods with AdjustableAspect Ratios, Langmuir, 14:2245-2255. 1998.

A method for the encapsulation of fluorescent molecule into silica“nanobubbles” has been reported in Makarova, Olga V., et al., Adsorptionand Encapsulation of Fluorescent Probes in Nanoparticles, J. Phys. Chem.B, 103:9080-9084, 1999. Bugnon, Philippe, (Bugnon, Philippe, Surfacetreatment of pigments. Treatment with inorganic materials, Progress inOrganic Coatings 29: 39-43, 1996) has reported novel treatments ofpigments with inorganic materials. Mikrajuddin, et al., (Mikrajuddin, etal., Stable pho to luminescence of zinc oxide quantum dots in silicananoparticles matrix prepared by the combined sol-gel and spray dryingmethod, Journal of Applied Physics, 89:11. 2001) reported a ZnO/SiO2nanocomposite with improved photoluminescence stability over ZnOcolloids.

A spray drying approach has been used to apply 15-nm-thick SiCbcontinuous coatings onto ZnS:Ag phosphor particles as described inVillalobos, Guillermo, R., et al., Protective Silica Coatings onZinc-Sulfide-Based Phosphor Particles, J. Am. Ceram. Soc.,85(8):2128-2130, 2002.

Iskandar et al. have reported the preparation of microencapsulatedpowders by an aerosol spray method. The powders prepared by mixing twotype of sols or sol-aqueous mixture precursor solution (Iskandar, Ferry,et al., Preparation of microencapsulated powders by an aerosol spraymethod and their optical properties, Advanced Powder Technol.14(31:349-367. 2003). Iskandar et al. (Control of the morphology of nanostructured particles prepared by the spray drying of a nanoparticle sol.J Colloid Interface Sci., 265(21:296-303. 2003) additionally describedthe parameters influencing particles morphology by spray drying ofsilica nanoparticle sol.

Silica coating using layer by layer technique has been described in Dun,Huijuan, et al., Eayer-by-Layer Self-Assembly of Multilayer ZirconiaNanoparticles on Silica Spheres for HPLC Packings, Anal, Chem.,76:5016-5023, 2004; Yuan, Junjie, et al., Organic Pigment ParticlesCoated with Colloidal Nano-Silica Particles via Layer-by-Layer Assembly,Chem. Mater., 17(41:3587-3594. 2005; Chung, Chau-Chyun, et al., AqueousSynthesis of Y2O2S:Eu/Silica Core-Shell Particles, J. Am. Ceram. Soc.,88(5): 1341-1344, 2005.

Y2O2:Eu red phosphor Powders coated with silica using sol-gel andheterocoagulation techniques were described in Jean, Jau-Ho, et al.,Y2025: Eu Red Phosphor Powders Coated with Silica, J. Am. Ceram. Soc.,83(8): 1928-1934, 2000.

Wilhelm, P., et al., (Wilhelm, P., et al, On-line tracking of thecoating of nanoscaled silica with titania nanoparticles viazeta-potential measurements, Journal of Colloid and Interface Science,293:88-92, 2006) reported nanoscaled spherical particles which weredirectly coated with titania nanoparticles by means of heterogeniccoagulation.

The interaction between colloidal silica particles and the surface ofZnS-type phosphors has been studied in Merikhi, J., et al., Adhesion ofColloidal SiCb Particles on ZnS-Type Phosphor Surfaces, Journal ofColloid and Interface Science, 228:121-126, 2000.

Sodium Silicate utilized to obtain a SiCb coating on particles has beendescribed in Wang, Hongzhi, et al., Effect of PolyelectrolyteDispersants on the Preparation of Silica-Coated Zinc Oxide Particles inAqueous Media, J. Am. Ceram. Soc., 85(81:1937-1940, 2002; U.S. Pat. Nos.2,885,366; 3,826,670.

The sources of silica gels and factors controlling gel characteristicswere described in Iler Ralph K., The Chemistry of Silica,Wiley-Interscience publication, 1979, pp. 510-533. U.S. Pat. No.6,303,290 describes the encapsulation of biomaterials in porousglass-like matrices prepared via an aqueous colloidal sol-gel process.This process includes entrapment of the biomaterial in silica cagesforms by controlling the gel characteristics.

JP02-002867 and JP 02-251240 disclose spherical particles madeprincipally of silica, prepared by coprecipitation on of silica and UVfilters such as benzophenone derivatives or dibenzoylmethane derivative,prepared in a water-in-oil emulsion.

U.S. Pat. No. 6,875,264 discloses a multilayer effect pigment includinga transparent substrate, a layer of high refractive index material onthe substrate, and alternating layers of low refractive index and highrefractive index materials on the first layer. The high refractive indexmaterial may be titanium dioxide and the low refractive index materialmay be silicon dioxide.

U.S. Pat. No. 6,090,399 discloses a controlled release compositioncomprising one or more biologically active compounds incorporated into ametal oxide glass having a porous matrix

U.S. Pat. Nos. 7,001,592 and 7,037,513 disclose a composition fortopical application, e.g., a body-wash, where the additive contains asol-gel encapsulated active either a sunscreen or a non-sunscreen. U.S.Pat. No. 7,052,913 discloses a biocompatible matrices, such as sol-gelsencapsulating a reaction center, which may be administered to a subjectfor conversion of prodrugs into biologically active agents.

U.S. Pat. Nos. 6,303,149, 6,238,650, 6,468,509, 6,436,375, US2005037087,US2002064541, and International publication Nos. WO 00/09652,WO00/72806, WO 01/80823, WO 03/03497, WO 03/039510, WO00/71084,WO05/009604, and WO04/81222, disclose sol-gel microcapsules and methodsfor their preparation. EP 0 934 773 and U.S. Pat. No. 6,337,089 teachmicrocapsules containing core material and a capsule wall made oforganopolysiloxane, and their production. EP 0 941 761 and U.S. Pat. No.6,251,313 also teach the preparation of microcapsules having shell wallsof organopolysiloxane. U.S. Pat. No. 4,931,362 describes a method offorming microcapsules or micromatrix bodies having an interiorwater-immiscible liquid phase containing an active, water-immiscibleingredient. Microcapsules prepared by a sol-gel process are alsodisclosed in GB2416524, U.S. Pat. No. 6,855,335, WO03/066209.

Another media, which can be utilized to protect sensitive ingredients,is doping within sol-gel matrices. In this method, monoliths, particlesor other forms (such as thin films) are prepared, and the activeingredient is immobilized in the pores of the sol-gel matrix. Thesol-gel matrix is doped with small amounts of the active ingredient.This method was utilized in WO98/31333, U.S. Pat. Nos. 6,495,352, and5,292,801.

Thus there is a widely recognized need and will be highly advantageousto have a new process for metal oxide coating of a solid water insolubleparticulate matter, enabling the growth of a metal oxide layer on saidsolid water insoluble particulate matter to the desired thickness andhaving the advantage of controlling and tuning of the thickness of themetal oxide layer. There is additionally a need for compositionsespecially for dermatological or agricultural use, characterized by theability to isolate the active agent from the surrounding (by reducingits leaching through the metal oxide coating layer) thus lowering theside effects and toxicity associated with the active agent, and yetwhich are efficient at controlling the release of the active agent tothe loci to be treated.

SUMMARY OF THE INVENTION

The present invention is based on the finding of a manner of obtaining athick and dense coating of metal oxide on a solid water-insolubleparticulate matter. The formation of the metal oxide layer by the newmethod is irreversible, i.e. it does not erode or disintegrate upondispersion in water. The new method further enables to obtain a moredense layer and is capable of fine tuning of the width of the metaloxide layer, thus allowing better control of the release of the activeingredient from the microparticles upon application on a surface (suchas skin or mucosal membrane, or pest-infested surface). The new methodcomprises treating the solid water-insoluble particulate matter with anionic additive, e.g. a first cationic additive in an aqueous medium toobtain a dispersion of said particulate matter having positive chargeson its surface; coating the particulate matter by precipitation of ametal oxide salt; and aging the coating layer. The coating is repeatedat least 4 more times, preferably 4 to about 1000 more times, morepreferably 4 to about 300 times, even more preferably 4 to about 100times. The aging step is conducted at the end of the process. Thus, theaging is not conducted between repeated coating steps (i.e. repeatedcoating steps of at least 4 more times), but only at the end of theprocess. The process includes additional steps as will be detailed belowsuch as treating the so formed coating with a surface adhering secondcationic additive to obtain positive charges on the coating, in order tomodify the surface charge of the metal oxide layer to make it reactivefor further coating by an additional metal oxide layer in a similarmanner to that described above. Alternatively, or in addition to saidcationic additive, a non-ionic, surface adhering additive (e.g. anon-ionic polymer) may be used. Without being bound to theory suchnon-ionic additive may function as an adhesive material allowingprecipitation of a further metal oxide layer on the coated metal oxidelayer. The process may further include for example a step of separatingthe coated particulate matter such as by filtration, centrifugation ordecantation; and optionally a step of washing and re-dispersing theobtained coated particulate matter in an aqueous medium.

The new method of preparation enables the formation and growth of athick layer or layers of a metal oxide coating on the particulatematter, with the ability of fine control of the width of the obtainedlayer. This is particularly advantageous for certain uses where theactive ingredient should be isolated, from its surroundings with anability to be gradually released through the metal oxide layer.Exemplary uses are dermatological or cosmetic uses as well as in thecase of pesticides for home, horticultural or agricultural use. The newmethod enables fine tuning and control of the thickness of the metaloxide layer.

Preferred is coating intended to achieve substantially the same or alarger therapeutic effect of the active agent and reduced side effectscompared to an uncoated composition of the active agent.

According to one aspect of the present invention there is provided aprocess for coating a solid, water-insoluble particulate matter, with ametal oxide comprising:

(a) contacting the solid, water-insoluble particulate matter with anionic additive and an aqueous medium to obtain a dispersion of saidparticulate matter having positive charges on its surface;

(b) subjecting the particulate matter to a coating procedure comprisingprecipitating a metal oxide salt onto the surface of the particulatematter to form a metal oxide layer thereon to thereby obtain particulatematter coated by a metal oxide coating layer;

(c) repeating step (b) at least 4 more times; and

(d) aging said coating layer.

According to another aspect of the present invention there is providedcoated particulate matter obtained by the process as described in thepresent invention.

According to yet another aspect of the present invention there isprovided a method for treating a surface condition in a subject,comprising topically administering onto the surface a compositioncomprising coated particulate matter as described in the presentinvention, the particular matter being a topically dermatologicallyactive agent.

According to additional aspect of the present invention there isprovided use of coated particular matter as described in the presentinvention, the particular matter being a topically dermatologicallyactive agent, for topical administration on the skin or mucosalmembrane.

According to a further aspect of the present invention there is provideda method for preventing, reducing, or eliminating pests at a locus,comprising applying to the locus of said pest a pesticidaly effectiveamount of a pesticidal composition comprising a coated particulatematter as described in the present invention, the particulate matterbeing a pesticide.

Also provided by the invention are particles comprising a particularmatter coated by a metal oxide layer wherein: (i) said metal oxide layerhas a width of 0.1-10 micron, and (ii) said particles are characterizedin that when tested in Dissolution Tester using Paddle Method in amedium, typically organic-based solvent such as acetonitrile, iso propylmiristate, ethanol, or methanol, in which said particulate matter issoluble, and a dissolution volume in which the concentration of theparticular matter is lower than the solubility of the particular matter,the time for releasing 50% w/w of the particulate matter from saidparticulars is at least two-fold higher, preferably three-fold higher,more preferably five-fold higher and most preferably ten-fold higher ascompared to the dissolution of the free form of the particulate matterhaving substantially the same particle size diameter as the particulatematter in said particles.

Further provided by the invention are particles comprising a corecomposed of a solid, water insoluble particulate matter; said core iscoated by a metal oxide layer; wherein said metal oxide layer issubstantially not in an amorphous and/or not in a crystalline form. Theterm “said metal oxide layer is substantially not in an amorphous and/ornot in a crystalline form” is meant to denote that distinct regions ofamorphous metal oxide (in case the metal oxide in its pure form isamorphous) or crystalline metal oxide (in case the metal oxide in itspure form contains crystalline material, or is purely crystalline)cannot be detected by methods such as X-Ray diffraction. Thenon-amorphous and/or non-crystalline metal oxide layer refers to aco-structured composite of metal oxide and an adhering additive. Suchadhering additive may be for example a polymer which interrupts theformation of continues regions of the metal oxide, thereby leading tothe non-amorphous and non crystalline metal oxide form. The nonamorphous and non crystalline metal oxide form is characterized by nothaving any X-ray diffraction peak specific to the metal oxide in itspure form. For example, if the metal oxide in its pure form isamorphous, a characteristic X-ray diffraction peak or peaks may bedetected. This may be the case, for example, in case of a particle witha pure metal oxide coating. In the case of the particles according tothis aspect of the disclosure, the characteristic X-ray diffractionpeak(s), specific to the amorphous form is absent, shifted, orflattened. An example are particles with a silica-based coating, whichwill have a different peak—namely absent, shifted, or flattened—ascompared to particles with an amorphous silica coating. In the case of ametal oxide which in its pure form contains crystalline regions, or ispurely crystalline, in the case of a composite coating a peak specificto the crystalline form is absent, shifted, or flattened. Thus, X-raydiffraction may serve to distinguish particles of this aspect of thedisclosure over others.

BRIEF DESCRIPTION TO DRAWINGS

FIG. 1 shows the release rate of BPO for sample SGT025, preparedaccording the coating procedure in Example 1, using step 2b: coatingoption #2. Number of repeating coating was 20, 30, 40. Aging wasconducted for 96 hours at 25 C. The release rate is compared to freeBPO.

FIG. 2 shows the release rate of BPO for sample SGT010, preparedaccording |the coating procedure in Example 1, using step 2a: coatingoption #1. Number of repeating coating was 20, 35. Aging was conductedfor 72 hours at 25 C. The release rate is compared to free BPO.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for coating a solid,water-insoluble particulate matter, with a metal oxide comprising:

(a) contacting the solid, water-insoluble particulate matter with anionic additive and an aqueous medium to obtain a dispersion of saidparticulate matter having positive charges on its surface;

(b) subjecting the particulate matter to a coating procedure comprisingprecipitating a metal oxide salt onto the surface of the particulatematter to form a metal oxide layer thereon thereby to obtain particulatematter coated by a metal oxide coating layer;

(c) repeating step (b) at least 4 more times; and

(d) aging said coating layer.

As used herein the term “solid, water-insoluble particulate matter”refers to a solid material having solubility in water of less than 1%w/w, typically less than 0.5% and at times less than 0.1% w/w at roomtemperature (20° C.).

The “solid, water-insoluble particulate matter” constitutes the “core”of the particles obtained by the process. The solid, water-insolubleparticulate matter, is preferably in such a state of subdivision that itcan be suspended in water, e.g. in the form of a finely-divided powderhaving a D90 (see definition below), preferably in the range of 0.3-50micron. Such a particulate matter can readily be suspended in an aqueoussystems by stirring, with or without the aid of a surfactant. The“solid, water-insoluble particulate matter” may be comprised of theactive ingredient per se or may be comprised of the active ingredientand excipients (e.g. solid carrier).

The terms “solid, water-insoluble particulate matter” and “particulatematter” will be used interchangeably.

In the present invention the terms “layer”, “coating” and similar terms,refer to a layer of metal oxide formed around a particle or particulatematter. The layer or coating may not always be complete or uniform andmay not necessarily lead to complete coverage of the particulate matteror particle surface. It is appreciated that upon repetition of thecoating steps as the coating process proceeds a more uniform coating andmore complete coverage of the particulate matter is obtained.

The term “dispersion” as used herein in step (a) of the process refersto a solid dispersion of the particulate matter in the aqueous medium.

Step (a) of the process may further comprise reducing the particle sizeof the particulate matter to the desired particle size for example bymilling or homogenization.

The core (i.e. solid, water insoluble particulate matter) may be of anyshape for example rod-like, plate-like, ellipsoidal, cubic, or sphericalshape.

Referring to size of particles will be through their D90 meaning that90% of the particles have the stated dimension or less (measured byvolume). Thus, for examples, for spherical particles stated to have adiameter of 10 micrometer {“microns”), this means that the particleshave a D90 of 10 microns. The D90 may be measured by laser diffraction.For particles having a shape other than spheres, the D90 refers to themean average of the diameter of a plurality of particles.

In the case of cores having a spherical shape, the diameter (D90) may bein the range of 0.3 to 90 microns, preferably 0.3 to 50 microns, morepreferably 1 to 50, even more preferably 5 to 30 microns.

By the term “D90 may be in the range of 0.3 to 90 microns” is meant that90% by volume of the particles (in this case the particle's core) may beless than or equal to a value in the range of 0.3 to 90 microns.

For generally cubic-shaped cores or cores having a shape resembling thatof a cube, the mean size of a side may be in the range 0.3 to 80microns, preferably 0.3 to 40 microns, more preferably 0.8 to 40, evenmore preferably 4 to 15 microns.

For rod-like shaped, ellipsoidal-shaped and plate-like shaped cores, thelargest dimension (that of the longest axis) is typically in the range10 to 100 microns, preferably 15 to 50 microns; and the smallestdimension is typically in the range 0.5 to 20 microns, and morepreferably 2 to 10 microns.

As used herein, unless otherwise indicated, the term “particle” refersto the metal oxide coated particulate matter.

It is appreciated that some of the particles obtained by the process mayat times be formed from two or more original particles of the solid,water-insoluble particulate matter and may accordingly include at timesmore than one core, such cores being separated from each other by ametal oxide region.

The core may be an organic or inorganic material. Preferably the core iscomposed of a material other than a metal oxide.

The weight of the solid, water-insoluble particulate matter (corematerial) based on the total weight of the particle may be in the range99%-50% w/w, more preferably in the range 97%-50% w/w. The core materialmay be in a crystalline form, amorphous form, or combination thereof.The core material may be a cosmetically, pharmaceutically or anagrochemical active ingredient.

Preferably step (c) of the process described above is repeated 4 toabout 1000 times. This means that preferably step (b) of the processdescribed above is repeated 4 to about 1000 times.

Preferably the process comprising repeating step (c) 4 to about 300times, and more preferably 4 to about 100 times. Even more preferablystep (c) of the process described above is repeated 5-80 times and mostpreferably 5-50 times. This means that preferably step (b) is repeatedas indicated above with respect to step (c).

By the term “repeated 4 to about 1000 times” is meant that the processmay be repeated 4, 5, 6, 7, 8, 9 . . . , etc. times up to and includingabout 1000 times.

According to a preferred embodiment of the present invention step (d)further comprising after aging, separating the coated particulate matterfrom the dispersing aqueous medium, such as by filtration,centrifugation or decantation and optionally rinsing and redispersingthe obtained coated particulate matter in an aqueous medium.

During the coating process it is preferred that at least 50% of thecontent the particulate matter (active agent) in the aqueous medium isin a solid state during the coating process.

According to a preferred embodiment of the present invention the processcomprising:

(a) contacting the solid, water-insoluble particulate matter, with afirst cationic additive and an aqueous medium to obtain a dispersion ofsaid particulate matter having positive charges on its surface;

(b) subjecting the particulate matter to a coating procedure comprisingprecipitating a metal oxide salt onto the surface of the particulatematter to form a metal oxide coating layer on the particulate matter;

(b1) in an aqueous medium, contacting the coated particulate matter witha surface adhering additive being one or both of (i) a second cationicadditive, and (ii) a non-ionic additive;

(b2) subjecting the particulate matter obtained in step (b1) to acoating procedure as in step (b);

(c) repeating steps (b1) and (b2) at least 3 more times; and

(d) aging the metal oxide coating layer.

Preferably the process comprising repeating step (c) 3 to about 1000times.

Preferably the process comprising repeating step (c) 3 to about 300times, and more preferably 3 to about 100 times.

As used herein by the term “repeating step (c) 3 to about 1000 times” ismeant that the process may be repeated 3, 4, 5, 6, 7, 8, 9, . . . etc.times up to and including about 1000 times.

This means that preferably steps (b1) and (b2) are repeated as indictedabove with respect to step (c).

Additionally according to a preferred embodiment of the presentinvention the process comprising:

(a) contacting the solid, water-insoluble particulate matter, with ananionic additive, a first cationic additive and an aqueous medium toobtain a dispersion of said particulate matter having positive chargeson its surface;

(b) subjecting the particulate matter to a coating procedure comprisingprecipitating a metal oxide salt onto the surface of the particulatematter to form a metal oxide coating layer on the particulate matter;

(b1) in an aqueous medium, contacting the coated particulate matter witha surface adhering additive being one or both of (i) a second cationicadditive, and (ii) a non-ionic additive;

(b2) subjecting the particulate matter obtained in step (b1) to acoating procedure as in step (b);

(c) repeating steps (b1) and (b2) at least 3 more times; and

(d) aging the metal oxide coating layer.

When an anionic additive and first cationic additive are used in step(a) of the process, preferably the anionic additive is added before thefirst cationic additive.

Step (c) may be repeated 3 to about 1000 times. Preferably step (c) isrepeated 3 to about 300 times, and more preferably 3 to about 100 times.This means that preferably steps (b1) and (b2) are repeated as indictedabove with respect to step (c).

The ionic additive (such as first cationic additive) used in step (a) ofthe process have a dual effect: to form positive charges on the surfaceof the particulate matter as will be described below, and also to serveas a wetting agent, thus allowing dispersion of the particulate matteras discrete core particles, where each core particle is individuallysuspended in the aqueous medium.

Step (a) of the process may be conducted for example by (i) contactingthe particulate matter with dry ionic additives and then suspending bothin an aqueous medium to obtain a dispersion of said particulate matterhaving positive charges on its surface, or alternatively by (ii)suspending the solid, water-insoluble particulate matter in an aqueousmedium comprising ionic additives to obtain a dispersion of saidparticulate matter having positive charges on its surface.

According to another preferred embodiment of the process may comprise(a) contacting the solid, water-insoluble particulate matter, with anionic additive selected from (i) an anionic additive; (ii) a firstcationic additive, and a combination thereof, and an aqueous medium toobtain a dispersion of said particulate matter having positive chargeson its surface; (b), (b1), (b2), (c), (d) are as described herein.

The concentration of the ionic additives in the dispersion can be about0.001% to about 30%, preferably about 0.01% to about 10% w/w and mostpreferably about 0.1% up to about 5% w/w. The solid content of the waterdispersion can be about 0.1% to about 80% w/w, preferably about 1% toabout 60% w/w most preferably about 3% to about 50% w/w.

The purpose of step (a) is to modify the electrical charge of theparticulate matter by using ionic additives such that it will be madereactive to the attachment of the metal oxide layer.

For preparing the core material of the particles, the particulate matterought to be suitably coated with an ionic additive (e.g. cationicadditive), such that it can be attached to the precipitated metal oxidesalt.

Preferably the ionic additive is selected from a cationic additive, ananionic additive, and a combination thereof. The cationic additive maybe a cationic surfactant and/or cationic polymer. The anionic additivemay be an anionic surfactant and/or anionic polymer.

The particulate matter is contacted with an ionic additive, for exampleby mixing it with a solution of a cationic surfactant and/or cationicpolymer or an anionic surfactant and a cationic additive (e.g. cationicsurfactant and/or cationic polymer). Cationic and anionic surfactantsare particularly effective in being adsorbed upon the surface of theparticulate matter. The ionic additive may also be anionic polymers usedin combination with a cationic additive. The cationic surfactant and/orthe cationic polymer and optionally further the anionic surfactant (oranionic polymer) need to be used in sufficient amount to providepositive charges on the surface of the particulate matter. A monolayerof the ionic additive is preferred, but the coating need not becontinuous. It is sufficient that there are at least spots of cationicadditive. These spots will then serve as anchors for the attachment ofthe metal oxide layer. It is preferred that there are fairly uniformdistribution of these anchoring points on the core surface so that asthe metal oxide layer builds up it will bridge over and be firmlyattached to the core.

According to one preferred embodiment said first and said secondcationic additive are the same.

According to another preferred embodiment said first and said secondcationic additive are different.

More preferably the first ionic additive is an anionic surfactant andthe second ionic additive is a cationic polymer

Most preferably the first cationic additive is a cationic surfactant andthe second cationic additive is a cationic polymer.

According to another preferred embodiment, the first cationic additiveis a cationic surfactant and the additive in step (b1) is a non-ionicadditive (e.g. a non-ionic polymer).

Preferably the coated particulate matter and the second cationicadditive are mixed, and most preferable said mixing is under vigorousstirring (e.g. mixer speed above 1000 rpm).

According to a preferred embodiment of the present invention the processfurther comprising following step (d): (e) separating the coatedparticulate matter from the aqueous medium and optionally rinsing andredispersing the coated particulate matter in an aqueous medium.

Preferably the separation of the coated particulate matter is conductedby a method such as filtration, centrifugation, decantation, dialysis,or by evaporation of the aqueous medium.

Additionally, according to a preferred embodiment of the presentinvention, step (b) comprises adding a metal oxide salt to the aqueousmedium; and optionally acidifying the aqueous medium.

Further according to a preferred embodiment of the present invention,step (b2) comprises adding a metal oxide salt to the aqueous medium; andoptionally acidifying the aqueous medium.

Preferably step (b1) further comprising adjusting the pH of thedispersion obtained in (b) to a value higher than the isoelectric pointof the metal oxide before adding the second cationic additive, morepreferably to a pH value of at least about 1 unit higher than theisoelectric point of the metal oxide, before adding the second cationicadditive.

Preferably step (b1) further comprising adjusting the pH of thedispersion obtained in (b) to a value higher than the isoelectric pointof the metal oxide before adding one or both of (i) a second cationicadditive, and (ii) a non-ionic additive, more preferably to a pH valueof at least about 1 unit higher than the isoelectric point of the metaloxide, before adding one or both of (i) a second cationic additive, and(ii) a nonionic additive.

For example, in case the metal oxide is silica (e.g. having anisoelectric point in the range 1.7-2.5) the preferred pH may be at leastin the range of about 2.5-6.5.

The purpose of the pH adjustment of the dispersion to a value higherthan the isoelectric point of the metal oxide is to form negativelycharged metal oxide on the particulate matter surface that will be boundto the positive charges of the second cationic additive thus enablingthe attachment of the second cationic additive to the surface of theparticulate matter.

The non-ionic additive is of a kind that adheres to the surface(“surfaceadherent”). An example is a non-ionic polymer. The non-ionicadditive may be used alone or in addition to the second cationicsurfactant. Without wishing to be bound by theory, the surface-adherentproperty may be through hydrogen-binding groups such as hydroxyl oramine groups. This allows adhesion of a further layer of metal oxide onthe preceding precipitated metal oxide layer.

Preferably the particulate matter/metal oxide salt weight ratio, in eachof the steps (b) or (b2) is about 5,000/1 to about 20/1, preferablyabout 5,000/1 to about 30/1, or about 5,000/1 to about 40/1, morepreferably about 1,000/1 to about 40/1, and most preferably about 500/1to about 80/1.

Preferably the particulate matter/cationic additive ratio, in step (b1)is about 25,000/1 to about 50/1, preferably about 5,000/1 to about100/1, and most preferably about 2000/1 to about 200/1.

According to preferred embodiment the particulate matter/metal oxidesalt weight ratio, in each of the steps (b) or (b2) is about 5,000/1 toabout 65/1, and more preferably about 1000/1 to about 100/1.

Preferably the particulate matter/cationic additive weight ratio, instep (b1) is about 10,000/1 to about 100/1, and more preferably about5000/1 to about 200/1.

The aging in step (d) is crucial for obtaining a strengthened and denselayer of metal oxide.

Preferably step (d) comprises raising the pH to a value in the range 3-9and mixing the suspension in this pH.

According to a preferred embodiment of the present invention step (d)comprises raising the pH to a value in the range 3-9 and mixing thesuspension in this pH for a period of at least 2 h.

According to a preferred embodiment of the present invention step (d)comprises raising the pH to a value in the range 3-9, preferably to arange of 5-7, and mixing, e.g. by stirring, the suspension (dispersion)in this pH range e.g. for a period of at least 2 h (two hours).Preferably stirring is for 2-96 h, more specifically 2-72 h, morepreferably at least 10 h (for example 10-72 h). The stirring ispreferably a gentle stirring, preferably in the range 200-500 rpm.

Upon completion of aging, the separation (e.g. filtration,centrifugation or decantation) will be easy to perform (due to the hardmetal oxide layer formed) and the obtained cake or concentrateddispersion will be easily re-dispersed in an aqueous medium to form adispersion of particles.

The purpose of aging in step (d) is to obtain a strengthened and denserlayer of metal oxide.

In the absence of the aging step a thinner and softer layer of metaloxide would be obtained since the metal oxide salt upon precipitationforms a gel layer of metal oxide which may disintegrate or erode uponseparation and washing or by mechanical stirring.

The aging may be conducted at a temp of 4-90° C., preferably at 15-60°C. and most preferably the aging is conducted at a temperature 20°C.-40° C.

Thus the repeated steps of coating and aging at the end of the processalso enable the growth of thicker and stronger layer of metal oxide. Theaging is not conducted between the repeated coating steps (i.e. betweenthe repeated coating step (b)), but only at the end of the process. Thusthe aging is conducted only at the end of the process described herein.

According to certain embodiments, the process may further compriseadding a colloidal metal oxide suspension, preferably aqueous-basedsuspension (comprising nanometric metal oxide (nanoparticles of metaloxide)) during the coating procedure. Preferably the colloidal metaloxide suspension is selected from colloidal silica suspension, colloidaltitania suspension, colloidal alumina suspension, colloidal zirconiasuspension, colloidal ZnO suspension, and mixtures thereof. Thecolloidal metal oxide suspension may be added during the coating process(e.g. in step (b) in one or more of its repeated steps). Preferably thesize of the nanometric metal oxide in diameter is in the range between5-1OO nm (average particle size diameter). The weight ratio of thenanometric metal oxide to the metal oxide salt may be in the range 95:5to 1:99 preferably 80:20 to 5:95 more preferably 70:30 to 10:90, mostpreferably about 60:40 to 20:80. The weight ratio of the nanometricmetal oxide to the metal oxide salt may be about 50:50.

According to other embodiments, the process does not include addition ofcolloidal metal oxide suspension during the coating process. Accordingto this embodiment nanometric metal oxide particles (nanoparticles ofmetal oxide) are not added during the coating process.

As used herein, the term “metal oxide coating layer” or “metal oxidelayer” encompasses the product of both a single processing step as wellas a product of the process in which the initially coated particles arefurther processed, by the repeated processing steps of step (c),described above.

The solid, water insoluble particulate matter may be a pharmaceutically,cosmetically, or agrochemical active ingredient.

Preferably the solid, water insoluble particulate matter is adermatological active agent.

Preferably the dermatological active agent is selected from antifungalagents, antibacterial agents, antiinflammatory agents, antipruriticagents, anti psoriatic agent, and anti acne agents. The dermatologicalagent may also be combinations of any of the above agents.

The antibacterial agents may be a bacteriostatic or bacteriocidal drug.

The dermatological active agent may be for example antifungal agentssuch as ketoconazole, bacteriostatic drugs such as metronidazole orerythromycin, bactericidal drugs such as bacitracin, corticosteroidssuch as mometasone furoate, methylprednisolone aceponate, prednicarbate,triamcinolone acetonide, fluocinonide, desoximetasone, bethasonevalerate or mometasone furoate, antipruritic agent such as doxepinhydrochloride, and anti acne agents such as benzoyl peroxide, azelaicacid, retinoids such as tretinoin (all trans retinoic acid), tazarotene,iso-tretinoin or adapalene.

More preferably the active agent (e.g. anti-acne agent) is selected frombenzoyl peroxide, retinoid, and mixtures thereof.

Most preferably the active agent (e.g. anti-acne agent) is benzoylperoxide.

The agrochemical agent may be a pesticide.

Pesticides which may be employed include a wide range of herbicides,nematocides, insecticides, acaricides, fungicides, plant growthpromoting or controlling chemicals and other crop treating productswhich are solids at ambient temperatures. One of ordinary skill in theart can find a listing of suitable pesticides by consulting referencessuch as the Ashgate Handbook of Pesticides and Agricultural Chemicals,G. W. A. Milne (ed.), Wiley Publishers (2000). Combinations of two ormore pesticides may also be employed.

Illustrative examples of the pesticides which may be employed areAzoxystrobin, Carbendazim, Chlorothalonil, Copper-oxychloride,Cyazofamid, Cymoxanil, Cyproconazole, Dimethomorph, Epoxiconazole,Fluazinam, Flusilazole, Flutolanil, Folutriafol, Kresoxim-methyl,Mancozeb, Maneb, Pencycuron, Pyraclostrobin, Tebuconazole,Thiophanate-methyl, Trifloxystrobin, Ziram, Aclonifen, Ametryn,Amicarbazone, Atrazine, Bentazone, Chlorimuron-ethyl, Cyhalofop-butyl,Ethalfluralin, Ethofumasate, Florasulam, Flufenacet, Flumetsulam,Fomesafen, Halosulfuron-methyl, Imazamox, Imazapic, Imazethapyr,Imazapyr, Imazaquin, Isoproturon, Isoxaflutole, Lactofen, Linuron,Mesotrione, Metamitron, Metazachlor, Metoxuron, Metribuzin,Metsulfuron-methyl, Oxyfluorfen, Pendimethalin, Prometryn, Propanil,Quinclorac, Quinmerac, Quizalofop-ethyl, Quizalofop-P-ethyl,Rimsulfuron, Simazine, Sulcotrione, Sulfentrazone, Sulfometuron-methyl,Sulfo sulfuron, Tebuthiuron, Thifensulfuron-methyl, Tralkoxydim,Triasulfuron, Triclopyr, Trifluralin, Abamectin, Acetamiprid, Aldicarb,Alphacypermethrin, Betacyfluthrin, Bifenthrin, Carbofuran, Chlorfenapyr,Chlorfluazuron, Chlorpyrifos, Cypermethrin, Deltamethrin, Endosulfan,Esfenvalerate, Fipronil, Imidacloprid, Indoxacarb, Lambda-cyhalothrin,Lufenuron, Methoxyfenozide, Novaluron, Oxamyl, Pirimicarb, Spinosad,Teflubenzuron, Thiacloprid, Thiamethoxam, Fenamiphos, Thidiazuron,Sulphur, and mixtures of any of the above.

Preferably the metal oxide is selected from Silica, Titania, Alumina,Zirconia, ZnO, and mixtures thereof. Most preferably the metal oxide issilica. The metal oxide salt is preferably an alkali metal oxide salt,e.g. a sodium or potassium salt.

According to a preferred embodiment the metal oxide salt is selectedfrom sodium silicate, potassium silicate, sodium aluminate, potassiumaluminate, sodium titanate, potassium titanate, sodium zirconate,potassium zirconate, and mixtures thereof. Most preferably the metaloxide salt is a silicate salt.

Further according to a preferred embodiment of the present invention theionic additive is selected from a cationic surfactant, anionicsurfactant, a cationic polymer, and mixtures thereof. When an anionicsurfactant is used, preferably a cationic additive is further added suchas a cationic surfactant and/or a cationic polymer.

Preferably the cationic additive is selected from a cationic surfactant,a cationic polymer, and mixtures thereof

According to a preferred embodiment the first cationic additive is acationic surfactant, and the second cationic additive is a cationicpolymer.

The first cationic additive is preferably a cationic surfactant.

Preferably the cationic surfactant is selected from monoalkylquaternaryammonium salts, dialkyl quaternary ammonium salts, and mixtures thereof.

Preferably the monoalkylquaternary ammonium salts are selected frombenzethonium chloride, benzalkonium chloride, cetyltrimethylammoniumchloride (CTAC), cetyltrimethylammonium bromide (CTAB),lauryltrimethylammonium chloride, stearyltrimethylammonium chloride,cetylpyridinium chloride, and mixtures thereof.

Most preferably the monoalkylquaternary ammonium salt iscetyltrimethylammonium chloride.

Preferably the dialkyl quaternary ammonium salt isdistearyldimethylammonium chloride.

Additional cationic surfactants which can be used are described in: JohnA. Wenninger et al. (Editors) International Cosmetic IngredientDictionary and Handbook (Eighth Edition 2000), Vol. 2 pp. 1140-1147,Published by The cosmetic, Toiletry, and Fragrance Association.

The ionic additive may be an anionic surfactant.

Preferably the anionic surfactant is selected from alkyl benzenesulphonic acids and salts, alkyl ether carboxylic acids and salts, alkylsulpho succinamates, alkyl sulphossucinates, alpha olefin sulphonates,aromatic hydrocarbon sulphonic acids and salts, fatty alcohol ethoxysulphates, fatty alcohol sulphates, phosphate esters, and mixturesthereof.

Preferably the alkyl benzene sulphonic acid salt is sodium dodecylbenzene sulphonate, the fatty alcohol sulphate is sodium laurylsulphate, the alkyl sulphossucinates is sodium dioctyl sulphossucinate,and mixtures thereof. The anionic surfactant may be mixtures of any ofthe above.

Additional anionic surfactants which can be used are described in: JohnA. Wenninger et al. (Editors) International Cosmetic IngredientDictionary and Handbook (Eighth Edition 2000), Vol. 2 pp. 1140-1147,Published by The cosmetic, Toiletry, and Fragrance Associationincorporated herein by reference in its entirety.

Preferably the weight ratio of the ionic additive to the water-insolubleparticulate matter is in the range 1:1000-1:10, more preferably in therange 1:200-1:50, most preferably about 1:100. The ratios indicatedabove refer to an ionic additive such as the first cationic additive orto the combination of a first cationic additive and an anionic additive.The second cationic additive may be a cationic polymer, a cationicsurfactant, or mixtures thereof. The cationic surfactant may be asdescribed above.

According to a preferred embodiment of the present invention the secondcationic additive is a cationic polymer.

Preferably the weight ratio of the first coated particulate matter (i.e.in step (b1)) to the second cationic additive is in the range of about25,000/1 to about 50/1, more preferably about 5,000/1 to about 100/1most preferably about 2000/1 to about 200/1.

Preferably the weight ratio of the further processed coated particulatematter (e.g. in the repeated steps described in step (c)) to the secondcationic additive is in the range of about 25,000/1 to about 50/1, morepreferably about 5,000/1 to about 100/1 most preferably about 2000/1 toabout 200/1.

Preferably the particulate matter/cationic additive weight ratio, instep (b1) is about 10,000/1 to about 100/1, and more preferably about5000/1 to about 200/1.

Preferably the weight ratio of the further processed coated particulatematter (e.g. in the repeated steps described in step (c)) to the secondcationic additive is in the range of about 10,000/1 to about 100/1, andmore preferably about 5000/1 to about 200/1.

In case a non-ionic additive (e.g. non-ionic polymer) is used alone orin addition to the second cationic additive, the weight ratios of the ofthe first coated particulate matter to the (i) non-ionic additive or(ii) a combination of a non-ionic additive and second cationic additive,and the weight ratios of the further processed coated particulate matterto the (i) non-ionic additive or (ii) the combination of the non-ionicadditive and second cationic additive, may be as indicated above withrespect to the second cationic additive.

Preferably the cationic polymer (of the first cationic additive orsecond cationic additive) is selected from poly(ethyleneimine) (PEI),poly(dimethyldiallylammonium chloride) (PDAC),poly(acrylamide-co-diallyl-dimethylammonium chloride)(polyquaternium-7), poly(allylamine hydrochloride) (PAH), Chitosan,polylysine, and mixtures thereof.

The second cationic polymer may also be a copolymer of non-ionic andionic monomers such as pyrrolidone/dimethylaminoethyl methacylatecopolymer.

According to another preferred embodiment of the present invention thesecond cationic additive is selected from colloidal alumina, colloidalceria (CeO2), colloidal alumina coated silica (such as Ludox CL,Sigma-Aldrich), and mixtures thereof.

The second cationic additive may be a colloidal metal oxide bearing apositive charge such as described above (e.g. colloidal alumina,colloidal ceria (CeO2), colloidal alumina coated silica, or mixturesthereof).

The non-ionic additive used in the process is preferably a non-ionicpolymer. The non-ionic polymer may be for example polyvinylalcohol,polyvinylpyrrolidone, and mixtures thereof.

Further according to a preferred embodiment of the present invention,the process further comprises drying the obtained coated particulatematter.

Still further according to a preferred embodiment of the presentinvention, the drying is by a method selected from spray drying,lyophilization, oven drying, vacuum drying, and fluidized bed.

Additionally, according to a preferred embodiment of the presentinvention, the process further comprises chemically modifying thesurface of the coated particulate matter.

The surface chemical modification preferably comprises modifying themetal oxide surface with organic groups, preferably hydrophobic groups.

Preferably process comprising attaching hydrophobic groups to thesurface of the metal oxide layer.

The purpose of attaching hydrophobic groups to the surface of the metaloxide layer is to control the water penetration rate into the particlesand consequently to control the release of the active agent from theparticles. Modifying the surface of the metal oxide layer by hydrophobicgroups enables to further control the release of the active agent fromthe particles, according to the desired rate.

The hydrophobic groups may be for example an alkyl silane, dialkylsilane, trialkyl silane, (such alkyl groups may be further substitutedwith one ore more flouro atoms), aryl silane (such as benzyl silane, orphenyl silane), diaryl silane, or triaryl silane.

Moreover according to a preferred embodiment of the present invention,the chemical surface modification comprises reacting silanol groups onthe surface of the metal oxide layer with precursors selected frommonohalotrialkyl silane such as chlortrimethylsilane, dihalodialkylsilane such as dichloro dimethyl silane, trihaloalkyl silane such astrichloromethylsilane, monoalkoxytrialkyl silane such as methoxy trimethyl silane, dialkoxydialkyl silane such as dimethoxydimethylsilane,trialkoxyalkyl silane such as trimethoxymethylsilane, aryltrihalo silanesuch as phenyltrichlorosilane, diaryldihalo silane such asdiphenyldichloro silane, triarylhalo silane such as triphenylchlorosilane, aryltrialkoxy silane such as phenyltrimethoxysilane,diaryldialkoxysilane such as diphenyldimethoxysilane,triarylalkoxysilane such as triphenylmethoxysilane, and mixturesthereof.

Preferably the alkyl group includes 1-18 carbon atoms, more preferably1-6 carbon atoms. Most preferably the alkyl is methyl. The alkyl groupsmay be substituted by one or more flouro atoms. Preferably the alkoxygroup includes 1-6 carbon atoms and more preferably 1-2 carbon atoms.

The halo group may be for example chloro, bromo, iodo, fluoro. Mostpreferably the halo groups are chloro and bromo.

The aryl is preferably phenyl or benzyl.

The precursors react with the silanol groups on the surface of the metaloxide layer to form a siloxane bond.

The attachment of the hydrophobic groups to the surface of the metaloxide layer can be performed by reacting the dried coated particulatematter with the above precursors. The procedure for attachinghydrophobic groups to the metal oxide can be conducted as follows: adried powder of coated particulate matter is suspended in an organicsolvent such as toluene. A precursor (hydrophobization reagent) from thelist above such as dimethyldichloro silane is added to the organic phase(mixture), optionally in the presence of a halogen scavenger such astrialkyl amine or triethanol amine. The organic mixture is refluxed forat least about 24 hours to obtain coverage of the metal oxide layer withthe hydrophobic groups via attachment of the hydrophobic groups to thesilanol groups on the surface of the metal oxide layer.

Further according to a preferred embodiment of the present invention theobtained metal oxide coating layer has a width (thickness) of about 0.1,0.2, 0.3, 0.5, 0.7, 1, 1.5, 2 or 5 micron or above, preferably up to 10micron.

The width of the metal oxide layer may be determined for example by aTransmission Electron Microscope or Confocal Microscope such that in acircular cross sectional area of the particle the smallest width is atleast e.g. 0.1 micron (the width is determined as the smallest distancefrom the surface of the particle (i.e. metal oxide surface) to thecore-metal oxide interface).

The invention additionally relates to the coated particulate matterobtained by the processes as described in the present invention.

According to a preferred embodiment of the present invention, the weightratio of the metal oxide to the solid, water-insoluble particulatematter, is in the range of 1:99 to 40:60. The weight ratio may also bein the range 1:99 to 50:50. Preferably the weight ratio of the metaloxide to the solid, water-insoluble particulate matter, is in the rangeof 10:90 to about 20:80. The weight ratio may also be as described inthe present invention.

According to a preferred embodiment of the present invention theparticles (coated particulate matter) have a diameter of 0.5-100 micron.More preferably the diameter of the particles is in the range 1-50micron and most preferably in the range 2-30 micron.

The particles may be useful for cosmetic or medical applications.

The particles may also be used in agricultural or polymeric industry.

The particles may be useful for any application wherein the activeingredient should be isolated, temporally or permanently from theambient surroundings.

It is appreciated that the particles of the present invention arecomposed of distinct regions of the metal oxide layer and the corematerial (i.e. the solid water insoluble particulate matter). The corematerial in newly prepared particles is preferably substantially free ofthe metal oxide and further the metal oxide layer is preferablysubstantially free of said core material, e.g. either as particledispersion (in the nanometric range of below 0.1 micron) of the waterinsoluble particulate matter or as molecular dispersion of said waterinsoluble particulate matter. Thus, according to a preferred embodimentof the present invention the metal oxide layer in newly preparedparticles, is substantially free of core material (either as moleculesor as nanometric particles). The term “substantially free” in thiscontext denotes that the concentration of the molecules of the corematerial or the concentration of the nanometric particles of the corematerial is negligible as compared to the metal oxide. Similarly, by theterm “the core material is substantially free of the metal oxide” ismeant that the concentration of the metal oxide in the core, isnegligible as compared to the core material.

Th invention further relates to a pharmaceutical, cosmetic orcosmeceutical composition for topical administration comprising acarrier; and a plurality of coated particulate matter obtained by theprocess described in the present invention, each of said particlescomprising a solid, water insoluble dermatologically active agent,coated by a metal oxide layer.

The carrier may be a cosmetic or pharmaceutically acceptable carrier.The coated dermatologically active agent is preferably dispersed in thecarrier.

The coated dermatological active agent may be easily dispersed orsuspended in a carrier or diluent.

Simple mixing with any suitable mixer or carrier is sufficient toachieve an effective dispersion. If necessary, high shear forces may beapplied to facilitate fast and efficient mixing of the coated particlesin the carrier.

The particles are preferably non-leaching when dispersed in a carrier,and most preferably non-leaching in an aqueous-based carrier.

By the term “non-leaching” it is meant that the leaching of theparticulate matter (active agent) from the particles into anaqueous-based liquid is less than 5% w/w, preferably less than 1% w/wand most preferably less than 0.5% w/w at room temperature (20° C.),under gentle agitation for 1 hour or until a steady state concentrationis achieved. Typically, said aqueous-based liquid is water. The valuesindicated above refer to the percentage of the active agent leached intoan aqueous medium relative to the initial amount of the active agent inthe particles. The leaching values indicated above refer preferably to adispersion having a concentration of the particulate matter in theaqueous medium higher than 0.1% w/w, more preferably higher than 1% w/w,and most preferably higher than 10% w/w.

The metal oxide coating obtained by the present invention is highlyadvantageous since it is capable of isolating the solid, water insolubleparticulate matter from its surrounding medium, and yet enables therelease the particulate matter upon application to the surface to betreated.

Preferably the dermatological active agent is selected from antifungalagents, antibacterial agents, antiinflammatory agents, antipruriticagents, anti psoriatic agent, anti acne agents, and mixtures thereof.

Preferably the anti-acne agent is selected from benzoyl peroxide, aretinoid, and mixtures thereof.

Preferably the retinoid is all trans retinoic acid (ATRA),iso-tretinoin, tazarotene or adapalene.

Most preferably the anti-acne agents are benzoyl peroxide (BPO) and alltrans retinoic acid (ATRA).

BPO and ATRA are particularly preferred compounds for coating with ametal oxide in accordance with the invention. The purpose of the BPO andATRA coating is to provide at least one of the following benefits: a) toreduce the skin irritation of the BPO and ATRA crystals, b) tosignificantly reduce side effects caused by BPO and ATRA in topicalformulations, c) to increase the dispersability of BPO and ATRA crystalsin aqueous solutions in the absence of surfactant, d) to prevent directcontact of the BPO and ATRA crystals from the skin, e) preventadditional crystal growth processes of BPO and ATRA after grinding, f)to increase the stability of the BPO and ATRA, g) to have goodcompatibility with other ingredients in the formulation, h) to produce asustained release mechanism of BPO and ATRA onto the skin.

According to a preferred embodiment of the present invention, the metaloxide is selected from Silica, Titania, Alumina, Zirconia, ZnO, andmixtures thereof. Most preferably the metal oxide is silica.

Further according to a preferred embodiment of the present invention,the weight ratio of said metal oxide to said solid, water-insolubleparticulate matter, is in the range 1:99 to 40:60. The weight ratio maybe in the range 3:97 to 50:50. The weight ratio of the metal oxide layerto the solid, water-insoluble particulate matter, may be also in therange 5:95 to 40:60, 10:90 to 40:60, 5:95 to 30:70, or 10:90 to 30:70.

Still further according to a preferred embodiment of the presentinvention, the weight ratio of said metal oxide to said solid,water-insoluble particulate matter, is in the range 10:90 to 20:80.

Moreover, according to a preferred embodiment of the present invention,the particles (coated particulate matter) have a diameter of 0.5-100micron.

The thickness of said metal oxide layer may be as described above.

Additionally, according to a preferred embodiment of the presentinvention, the thickness of said metal oxide layer is in the range0.1-10 micron.

Further according to another preferred embodiment of the presentinvention, the thickness of said metal oxide layer is in the range0.3-10 micron.

The carrier may be in the form of ointment, a cream, a lotion, an oil,an emulsion, a gel, a paste, a milk, an aerosol, a powder, a foam, awash. Most preferably the carrier is in the form of a gel or a creammore preferably oil-in-water cream. Most preferably the dispersing phase(i.e. the carrier) is aqueous based and comprises water as dispersingmedium.

As disclosed herein the composition may be for the treatment of adisease or condition selected from acne, infection, inflammation,pruritis, psoriasis, seborrhea, contact dermatitis, rosacea, and acombination thereof.

Further according to a preferred embodiment of the present invention,the dermatological agent is selected from antifungal agents,antibacterial agents, antiinflammatory agents, antipruritic agents, antipsoriatic agent, and anti acne agents.

The antifungal agents, antibacterial agents, antiinflammatory agents,antipruritic agents, anti psoriatic agent, and anti acne agents may beas described in the present invention above.

Most preferably the dermatological active agent is an anti-acne agent.

Moreover according to a preferred embodiment of the present invention,the anti acne agent is selected from benzoyl peroxide, retinoid, andmixture thereof.

Most preferably the anti-acne agent is selected from benzoyl peroxide,tretinoin (ATRA), and mixtures thereof.

According to a preferred embodiment of the present invention the metaloxide is selected from Silica, Titania, Alumina, Zirconia, ZnO, andmixtures thereof. Additionally according to a preferred embodiment ofthe present invention, the weight ratio of said metal oxide to saidsolid, water-insoluble dermatological active agent, is in the range 1:99to 40:60. The weight ratio of the metal oxide layer to the solid,water-insoluble particulate matter, may be also in the range 1:99 to40:60, 5:95 to 40:60, 5:95 to 30:70, or 10:90 to 30:70.

Further according to a preferred embodiment of the present invention,the weight ratio of said metal oxide to the solid, water-insolubleparticulate matter, is in the range 10:90 to 20:80. The weight ratiosmay also be as detailed above with respect to the weight ratio of themetal oxide to the solid, water-insoluble particulate matter.

Moreover, according to a preferred embodiment of the present invention,the particles have a diameter of 0.5-100 micron. Preferably theparticles have a diameter of 0.8-100 micron, more preferably 1-50 micronand most preferably 5-30 micron.

Additionally, according to a preferred embodiment of the presentinvention, the thickness of said metal oxide layer is in the range0.1-10 micron. The thickness may be as defined above in relation to theprocess. Typical thickness is about 0.1-3 micron, preferably about 0.1-1micron. The thickness of the metal oxide layer may also be in the rangeabout 0.3 to 3 micron, and most preferably about 0.3 to 2 micron.

According to a preferred embodiment of the present invention, thecarrier is in the form of an ointment, a cream, a lotion, an oil, anemulsion, a gel, a paste, a milk, an aerosol, a powder, a foam, or awash.

Also disclosed is a method for treating a surface condition in asubject, comprising topically administering onto the surface acomposition comprising a coated particulate matter as described in thepresent invention, the particulate matter being a topicallydermatologically active agent.

The coated particulate matter may be obtained by the process of thepresent invention.

It is appreciated that the compositions may comprise a plurality ofcoated particulate matter.

Preferably the subject is a mammal, and most preferably the mammal is ahuman.

The term “treating” or “treatment” as used herein includes any treatmentof a condition (disease or disorder) associated with a patient's bodysurface such as the skin or mucosal membrane, and includes inhibitingthe disease or disorder (i.e. arresting its development), relieving thedisease or disorder (i.e. causing regression of the disease ordisorder), or relieving the conditions caused by the disease (i.e.symptoms of the disease). The concentrations of the dermatologicalagents that can be used for treatment of a specific disease or disordermay be as described in The Merck index an encyclopedia of chemical,drugs, and biologicals/The Merck index an encyclopedia of chemical,drugs, and biologicals. Rahway, N.J.; Merck & Co; 1989., incorporatedherein by reference in its entirety.

Although individual needs may vary, determination of optimal ranges foreffective amounts of the compositions is within the skill of the art.Generally, the dosage required to provide an effective amount of apharmaceutical composition, which can be adjusted by one skilled in theart, will vary depending on the age, health, physical condition, weight,type and extent of the disease or disorder of the recipient, frequencyof treatment, the nature of concurrent therapy (if any) and the natureand scope of the desired effect(s).

According to a preferred embodiment of the present disclosure, thesurface of a subject body is skin or mucosal membrane.

The surface condition may be a disease or disorder selected from acne,infection, inflammation, pruritis, psoriasis, seborrhea, contactdermatitis, rosacea, and a combination thereof.

According to a preferred embodiment of the present disclosure, the metaloxide layer releases the particulate matter following topicalapplication (administration). Preferably the solid, water insolubleparticulate matter is a dermatological active agent as described above,more preferably an anti-acne agent, and most preferably thedermatological active agent (e.g. anti acne agent) is benzoyl peroxide.

According to another preferred embodiment the dermatological activeagent (e.g. anti acne agent) is a retinoid (preferably tretinoin).

Without being bound to theory it is assumed that benzoyl peroxide isreleased from the particles through the metal oxide coating layer byextraction by lipids available on the skin. Upon application on theskin, it is assumed that the skin lipids diffuse through the metal oxidelayer and extract the benzoyl peroxide present in the core. Otherdermatological agents may be similarly released from the particles.

The invention further relates to the use of coated particulate matter asdescribed herein, the particulate matter being a topicallydermatologically active agent, for the preparation of a medicament fortopical administration on the skin or mucosal membrane.

The topical administration is preferably for treating a disease ordisorder selected from acne, psoriasis, seborrhea, rosacea contactdermatitis, infection, inflammation, pruritis, and any combinationthereof.

According to a preferred embodiment of the present disclosure, thesurface of the metal oxide later of the coated particulate matter may bechemically modified by organic groups, preferably hydrophobic groups,attached to its surface.

The hydrophobic groups may be for example an alkyl groups (such alkylgroups may be further substituted with one ore more flouro atoms), arylgroups (such as benzyl or phenyl), and combinations thereof. The groupsmay be as described above with respect to the process.

Also disclosed are particles comprising a particular matter coated by ametal oxide layer wherein: (i) said metal oxide layer has a width of0.1-10 micron, and (ii) said particles are characterized in that whentested in Dissolution Tester using Paddle Method in a medium, typicallyorganic-based solvent such as acetonitrile, iso propyl miristate,ethanol, or methanol, in which said particulate matter is soluble, and adissolution volume in which the concentration of the particular matteris lower than the solubility of the particular matter, the time forreleasing 50% w/w of the particulate matter from said particulars is atleast two-fold higher, preferably at least three-fold higher, preferablyat least four-fold, more preferably at least five-fold higher and mostpreferably at least ten-fold higher as compared to the dissolution ofthe free form of the particulate matter having substantially the sameparticle size diameter as the particulate matter in said particles.

The dissolution of the free form of the particulate matter is measuredunder the same conditions as the coated particulate matter. The time forreleasing 50% w/w of the particulate matter (active agent) from theparticles is compared to the time of 50% w/w dissolution of the freeform. Preferably the dissolution volume is such that the concentrationof the particulate matter is lower than at least half of the solubilityof the particulate matter. The “solubility” relates to the solubility ofthe particulate matter (active ingredient) in the dissolution medium(e.g. an organic-based solvent such as acetonitrile, iso propylmiristate, ethanol or methanol). It is appreciated that the dissolutionvolume will also depend on the detection level of the analytical method.The dissolution may be conducted at a temperature of 20 C-40 C. Thedissolution may be conducted at a paddle rate of 50-200 rpm.

Pesticide Compositions and Uses

In one aspect, the present disclosure is directed to pesticidalcompositions comprising the coated pesticides described above.Typically, such compositions are comprised of the coated pesticide andan agriculturally acceptable carrier. Such carriers are well known inthe art and may be solids or liquids.

Other Components

To the extent that the compositions contain other components, thesecomponents make up minor portions of the composition. Minor componentsmay also include free pesticide, which has not been incorporated intothe coated pesticide. In addition to the other components listed herein,the compositions may also contain carriers, such as water or othersolvents in amounts for example equal to or greater than the majorcomponents.

The coated pesticides may be formulated and/or applied with one or moresecond compounds. Such combinations may provide certain advantages, suchas, without limitation, exhibiting synergistic effects for greatercontrol of pests, reducing rates of application of pesticide therebyminimizing any impact to the environment and to worker safety,controlling a broader spectrum of pests, resistance of crop plants tophytotoxicity, and improving tolerance by non-pest species, such asmammals and fish.

Second compounds include, without limitation, other pesticides,fertilizers, soil conditioners, or other agricultural chemicals. Thecompositions may also contain additional surface active compounds asdispersants. Typical wetting, dispersing or emulsifying agents used inagricultural formulations include, but are not limited to, the alkyl andalkylaryl sulfonates and sulfates and their sodium salts; alkylarylpolyether alcohols; sulfated higher alcohols; polyethylene oxides;sulfonated animal and vegetable oils; sulfonated petroleum oils; fattyacid esters of polyhydric alcohols and the ethylene oxide additionproducts of such esters; and the addition product of long-chainmercaptans and ethylene oxide. Many other types of useful surface-activeagents are available in commerce. Surface-active agents, when used,normally comprise 1 to 20% weight of the composition.

One skilled in the art will, of course, recognize that the formulationand mode of application of a pesticide may affect the activity of thematerial in a given application. Thus, for agricultural use, the presentcoated pesticides may be formulated as a granular of relatively largeparticle size (for example, 8/16 or 4/8 US Mesh) (e.g. agglomerates ofcoated particulate matter of the pesticide that may redisperse in waterto the primary coated particulate matter), as water-dispersiblegranules, as powdery dusts, as wettable powders, as suspensionconcentrates, as capsule suspension (coated particulate matter, insuspension), or as any other known types of agriculturally-usefulformulations, depending on the desired mode of application. They may beapplied in the dry state (e.g., as granules, powders, or tablets) orthey may be formulated as concentrates (e.g., solid, liquid, gel) thatmay be diluted to form stable dispersions (suspensions).

Concentrates

The compositions may be formulated as concentrates by techniques knownto one of ordinary skill in the art. If the composition is to beformulated as a solid, a filler such as Attaclay may be added to improvethe rigidity of the granule.

The coated pesticides and pesticidal formulations may be stored andhandled as solids which are dispersible into stable aqueous emulsions ordispersions prior to application. The dispersions allow uniformapplication from water. This is particularly advantageous at the fieldpoint of use, where normal admixing in water is all that is requiredbefore application.

The compositions may also be in the form of wettable powders. Wettablepowders are finely divided particles that disperse readily in water orother dispersant. The wettable powder is ultimately applied to the locuswhere pest control is needed either as a dry dust or as a dispersion inwater or other liquid. Typical carriers for wettable powders includeFuller's earth, kaolin clays, silicas, and other highly absorbent,readily wet inorganic diluents. Wettable powders normally are preparedto contain about 5-80% of pesticide, depending on the absorbency of thecarrier, and usually also contain a small amount of a wetting,dispersing or emulsifying agent to facilitate dispersion. For example, auseful wettable powder formulation contains 80.0 parts of the pesticidalcompound, 17.9 parts of clay and 1.0 part of sodium lignosulfonate and0.3 part of sulfonated aliphatic polyester as wetting agents. Additionalwetting agent and/or oil will frequently be added to a tank mix tofacilitate dispersion on the foliage of the plant.

Water-Dispersible Granules (WDG or DG) are dry compositions of thecoated pesticide that will disperse in water yielding a dispersion ofprimary particles. Pesticide contents may range from 10-70% w/w.Polymers are used as dispersants (polyacrylate salts and lignosulfonatesalts) and as binders to hold the granule together. Advantages of thedry product are that less potential for hydrolysis exists and highpesticide content may be achievable. Disadvantages are a more complexprocess involving milling blending extrusion and drying. Usuallyexcipients are solids in this formulation.

Other useful formulations for the pesticidal compositions includesuspo-emulsions, flowable formulations, and suspension concentrates.

Flowable formulations consist of particles of the pesticide complex(coated particulate matter of the pesticide) suspended in a liquidcarrier, generally water. Flowables, may include a small amount of asurfactant as a wetting agent and dispersants that are generally anionicor nonionic, and will typically contain pesticides in the range of 5% to95%, frequently from 10 to 50%, by weight of the composition. Forapplication, flowables may be diluted in water or other liquid vehicleand are normally applied as a spray to the area to be treated.

Suspension concentrates (SC) are dispersions of finely divided (2-15micron) water-insoluble solid particles of the pesticide complex inwater. Pesticide contents range from 8-50% w/w. They are pourable,easily dispersible in water and should be stable to settling in thepackage. Polymers such as xanthan gum are used to prevent settling byincreasing the yield stress of the suspension. Some polymericdispersants, such as polyacrylic acid salts, are used. The dispersionsmay be stabilized against flocculation by use of polymers such asmethacrylate grafted with polyethylene glycol (Atlox). Ethyleneoxide/propylene oxide copolymers may be used to provide somestabilization after dilution.

Suspo-emulsions (SE) are dispersions of water immiscible liquids andfinely divided (2-15 micron) water-insoluble solid particles of thepesticide complex (coated particulate matter of the pesticide) in water.Pesticide contents range from 8-50% w/w. They are pourable, easilydispersible in water and should be stable to settling in the package.They contain several surfactants, in order to both stabilize theparticles and emulsify the liquids. Some polymeric dispersants, such aspolyacrylic acid salts, are used. SEs, like SCs, may be stabilizedagainst flocculation by use of polymers such as methacrylate graftedwith polyethylene glycol (Atlox). Ethylene oxide/propylene oxidecopolymers may be used to provide some stabilization after dilution.

Useful formulations include suspensions of the coated pesticide in arelatively non-volatile solvent such as water, corn oil, kerosene,propylene glycol, or other suitable solvents. Granular formulations,wherein the coated pesticide is carried on relative coarse particles,are of particular utility for aerial distribution or for penetration ofcover crop canopy. Pressurized sprays, typically aerosols wherein thecoated pesticide is dispersed in finely divided form as a result ofvaporization of a low-boiling dispersant solvent carrier may also beused. Water-dispersible granules are free flowing, non-dusty, andreadily water dispersible. In use by the farmer on the field, thegranular formulations, suspo-emulsions, flowable concentrates, etc., maybe diluted with water to give a concentration of pesticide in the rangeof e.g., 0.2-2%.

Method of Controlling Pests

In a further aspect, this disclosure is directed to a method ofcontrolling pests comprising applying to the locus of such pests apesticidally effective amount of the pesticidal compositions describedherein. Such locus may be where pests are present or are likely tobecome present.

Thus the disclosure additionally relates to a method for preventing,reducing, or eliminating pests at a locus, comprising applying to thelocus of said pest a pesticidaly effective amount of a pesticidalcomposition comprising a coated particulate matter as described hereinthe particulate matter being a pesticide.

According to preferred embodiment the method is for preventing pestinfestation at a locus, comprising introducing said coated particulatematter onto a surface or into a substrate prone to pest attack.

The locus may be any location where pests are found or are expected tobe found for example foliage, soil or porous surfaces such as cement,wood, ceramics and similar surfaces.

The pesticide may be as described herein. Preferably the pesticide isselected from carbofuran, imidacloprid, thiamethoxam, tebuconazole,indoxacarb and pyrethroids including bifenthrin, cypermethrin,alphacypermethrin, deltamethrin, and lambda-cyhalothrin.

In applying the compositions, whether formulated alone or with otheragricultural chemicals, an effective amount and concentration of theactive compound is of course employed; the amount may vary in the rangeof, e.g. about 0.001 to about 3 kg/ha, preferably about 0.03 to about 2kg/ha. For field use, where there are losses of pesticide, higherapplication rates (e.g., four times the rates mentioned above) may beemployed.

The pesticidal compositions may be applied either as water-dilutedsprays, or dusts, or granules to the areas in which suppression of pestsis desired. These formulations may contain as little as 0.1% to as muchas 35% or more by weight of pesticide. Dusts are free flowing admixturesof the pesticide compositions with finely divided solids such as talc,natural clays, kieselguhr, flours such as walnut shell and cottonseedflours, and other organic and inorganic solids which act as dispersantsand carriers for the pesticide. These finely divided solids have anaverage particle size of less than about 50 microns. A typical dustformulation useful herein is one containing 1.0 part or less of thepesticidal composition and 99.0 parts of talc.

Different application methods are used for the pesticide formulationsdepending on the target pest, e.g., weed, fungus, or insect, and on thetype of crop being treated. Application of pesticide may be by sprayingsolutions, emulsions or dispersions of finely divided pesticide complexto achieve accurate and even concentration over the entire treated areaor target. Usually, the water used to dilute the pesticide compositionin the spray mixture amounts to approximately 5-80 gallons per acre andthe active ingredient amount may range approximately from 20 to 1000grams per acre.

Pesticides may also be applied by broadcast spreading of granularformulations using machinery to achieve even distribution over theentire target. The coated pesticide may be incorporated into granularformulations by using a sticker (additional surfactant, polymersolution, or latex) to attach the pesticide to an inert support. Othergranules are prepared by extrusion of powdered pesticide complex withinert powdered ingredients, water, binders, and dispersants to formgranules that are subsequently dried. Pre-formed granular supports areoften used to absorb liquid pesticide or solutions of the pesticide.

It is appreciated that the coated particulate matter, coating metaloxide layer, particulate matter, etc. described in a particular aspectmay be characterized by the various features, properties, etc. asdescribed in the other aspects.

EXAMPLES

In the examples below, all % values referring to a solution are in(w/w). All % values, referring to dispersions are in (w/w).

All solutions used in the examples below unless otherwise stated referto an aqueous solution of the indicated ingredient.

Example #1: Silica Coating of BPO

Step 1: Milling:

110 g. of hydrous BPO 75% (USP grade from Sigma) were suspended in 152g. of 0.4% CTAC solution containing 0.001% silicon antifoam. The BPO wasmilled using a stator rotor mixer (Kinematika polytron 6100 operated at15,000 rpm/25 m/s). The milling was stopped when the particle sizedistribution (PSD) of the suspension was d(0.9)<35|im or the temperaturehas reached 50 C. The final suspension was cooled to room temperature.

Step 2a: Coating Option #1:

During the coating procedure the suspension was stirred with amechanical dissolver, 80 mm, at 500 RPM at all times. The pH of themilled BPO suspension was corrected to 8 using NaOH 5N solution. Aportion of 1 g of 15% sodium silicate solution (15% w/w as SiO2) wasadded and the suspension was stirred for 5 min. A portion of 1 g of 3%Polyquaternium 7 was added and the suspension was stirred for 5 min. pHwas adjusted to 6-7 using 5N HCl solution.

This procedure was repeated for 5-100 times in order to create a seriesof silica layers around BPO having different thickness.

Step 2b:

coating option #2: During the coating procedure the suspension wasstirred with a mechanical dissolver, 80 mm, at 500 RPM at all times. ThepH of the milled BPO suspension was corrected to 8 using NaOH 5Nsolution. A portion of 2.5 g of 15% sodium silicate solution (15% w/w asSiO2) was added and the suspension was stirred for 5 min. A portion of2.5 g of 3% Polyquaternium 7 was added and the suspension was stirredfor 5 min. pH was adjusted to 6-7 using 5N HCl solution.

This procedure was repeated for 5-100 times in order to create a seriesof silica layers around BPO having different thickness.

The aging step: The coated BPO suspension at pH 6.5 was kept for agingat room temperature (25 C+/−2) under gentle agitation for 24 hrs.

Example #2: Analytical Evaluation of the BPO Release

The release profile of BPO out of the silica shell was done in awater/Acetonitrile solution, which is capable of dissolving BPO. Themethod is based on the strong oxidation properties of BPO. BPO reactswith potassium iodine (KI) ions to form 12, which gives a colorreaction. 12 is than reduces back to T using sodium thiosulfate (ST S)to eliminate the color. Each 12.11 mg of oxidizing BPO was reduced by 1ml of 0.1M STS.

Solution A is composed of deionized water, acetone, 0.1M STS solutionand KI. The following table includes the ratios between the componentsin order to distinguish a certain % of released BPO.

% released % % 0.IM % % dionized BPO acetone STS soln. KI water 10 603.67 4.5 31.83 20 60 7.34 4.5 28.16 30 60 11.01 4.5 24.49 50 60 18.354.5 17.15 70 60 25.69 4.5 9.81 90 60 33.03 4.5 2.47

Suspension B, preparation of BPO: weigh 200 mg of BPO as 100% (1 gas 20%suspension) into 5 ml measuring bottle and fill with deionized water upto 5 ml.

Procedure: Into 50 ml glass beaker add 40 ml of solution A and the 5 mlof suspension B and measure the time for yellow color appearance.

The following table summarizes the results obtained for encapsulated(coated) BPO as described in example #1.

Sample CS #oEC ATm ATp *10 *20 *30 *50 *70 *90 Free BPO — 0 0 — 0.5 1SGT010 2a 20 72 25 1.2 3 4 7 7.5 7.66 SGT010 2a 35 72 25 2.2 5 11 17 2426 SGT025 2b 20 96 25 3 7 10.3 19.3 28 29.5 SGT025 2b 30 96 25 4.6 12.323 40 60 68 SGT025 2b 40 96 25 7 25 32 69 113 123 SGT025 2b 40 96 40 721 47 80 140 170 #oEC—number of repeating coating as described inexample #1 CS—coating step as described in example #1 ATm—aging time inhours ATp—aging temperature in Celsius. *(10, 20 . . .) - time (in min.)for (10, 20 . . .) % of BPO released from the capsule (coated BPO).

The release rates of BPO of Samples SGT 025 and SGT 010 are shown inFIGS. 1 and 2.

Discussion:

It is clearly shown that the higher the amount of silica added perencapsulation (coating) cycle and/or the higher the number of coatingcycles, the longer the time for BPO release.

Example #3: Silica Coating of Tretinoin (ATRA

Step 1: Milling:

75 g. of all trans Retinoic acid (ATRA) (USP grade from Rhodia) aresuspended in 250 g. of 0.3% CT AC solution containing 0.001% siliconantifoam. The ATRA is milled using a M-110Y micro fluidizer processor(Microfluidics) at 15,000 psi. The milling is stopped when the particlesize distribution (PSD) of the suspension is d(0.9)<20|im. Thetemperature is kept below 30 C at all times.

Step 2: Coating:

During the coating procedure the suspension is stirred with a mechanicaldissolver, 80 mm, at 500 RPM at all times. The pH of the milled ATRAsuspension is corrected to about 4 using HCl 5N solution. A portion of0.5 g of 15% sodium silicate solution (15% w/w as SiCh) is added and thesuspension is stirred for 5 min. A portion of 0.5 g of 3% Polyquaternium7 is added and the suspension is stirred for 5 min. pH is readjusted toabout 4 using 5N HCl solution.

This procedure is repeated for 5-100 times in order to create a seriesof silica layers around ATRA having different thicknesses.

The Aging Step:

The coated ATRA suspension at pH 4.5 is kept for aging at roomtemperature under gentle agitation for 24 hrs.

Example #4: Silica Coating Using Anionic Surfactant

Step 1: Milling:

110 g. of hydrous BPO 75% (USP grade from Sigma) were suspended in 152g. of 0.4% sodium dodecyl sulphonate (SDS) solution containing 0.005%silicon antifoam. The BPO was milled using a stator rotor mixer(Kinematika polytron 6100 operated at 15,000 rpm/25 m/s). The millingwas stopped when the particle size distribution (PSD) of the suspensionwas d(0.9)<35|im or the temperature has reached 50 C. The finalsuspension was cooled to room temperature and a portion of 1-2.5 g of 3%Polyquaternium 7 was added and the suspension was stirred for 5 min.

Step 2a: Coating Option #1:

During the coating procedure the suspension was stirred with amechanical dissolver, 80 mm, at 500 RPM at all times. The pH of themilled BPO suspension was corrected to 8 using NaOH 5N solution. Aportion of 1 g of 15% sodium silicate solution (15% w/w as SiO2) wasadded and the suspension was stirred for 5 min. A portion of 1 g of 3%Polyquaternium 7 was added and the suspension was stirred for 5 min. pHwas adjusted to 6-7 using 5N HCl solution.

This procedure was repeated for 5-100 times in order to create a seriesof silica layers around BPO having different thickness.

Step 2b: Coating Option #2:

During the coating procedure the suspension was stirred with amechanical dissolver, 80 mm, at 500 RPM at all times. The pH of themilled BPO suspension was corrected to 8 using NaOH 5N solution. Aportion of 2.5 g of 15% sodium silicate solution (15% w/w as SiO2) wasadded and the suspension was stirred for 5 min. A portion of 2.5 g of 3%Polyquaternium 7 was added and the suspension was stirred for 5 min. pHwas adjusted to 6-7 using 5N HCl solution.

This procedure was repeated for 5-100 times in order to create a seriesof silica layers around BPO having different thickness.

The Aging Step:

The coated BPO suspension at pH 6.5 was kept for aging at roomtemperature (25 C+/−2) under gentle agitation for 24 hrs.

Example #5: Silica Coating of Tretinoin (ATRA), Using Non-Ionic Polymer

Step 1: Milling:

12.5 g. of tretinoin were suspended in 250 g. of 0.3% CTAC solutioncontaining 7.5 g BHT. The tretinoin was milled using a M-110Ymicrofluidizer processor (Microfluidics) at 15,000 psi. The milling wasstopped when the particle size distribution (PSD) of the suspension wasd(0.9)<13|im. The temperature has kept below 30 C at all times.

Step 2: Coating:

During the coating procedure the suspension was stirred with amechanical stirrer at all times. The pH of the milled ATRA suspensionwas about 3.5. A portion of 1 g of 15% sodium silicate solution (15% w/was SiCb) was added and the suspension was stirred for 5 min. HCl 1 M wasadded until the pH of the solution was about 3. A portion of 1 g of 1%polyvinyl alcohol water solution was added and the suspension wasstirred for 5 min.

This procedure was repeated 50 times in order to create silica layersaround ATRA.

The Aging Step:

The coated tretinoin suspension was kept for aging at room temperatureat pH 3 under gentle agitation for 24 hrs.

Example #6: Silica Coating of Bifenthrin Using Cationic Polymer

3.58 grams of cetyltrimethylammonium chloride (CTAC) (29% w/w aqueoussolution) were added to 196.5 grams of deionized water in a 1 literflask. 50.5 grams of dry milled bifenthrin technical (having an averageparticle size of about 15 microns) were added, and the mixture washomogenized using a Polytron PT 6100 Homogenizer. 216 grams of theresulting dispersion were transferred to a Mettler Toledo LabMaxAutomatic Lab Reactor.

1.8 grams of sodium silicate (25% w/w aqueous solution) were added andthe mixture was stirred for 5 minutes. The pH was adjusted to 7.0 by theaddition of 5 M HCl. The mixture was stirred for an additional 2minutes, and 3 grams of poly(acrylamide-co-diallyldimethylammoniumchloride (3% w/w aqueous solution)(PDAC) were added. The mixture wasstirred for 5 minutes.

The process in the above paragraph (commencing with the addition of thesodium silicate) was repeated 49 times. Then, after 5 minutes ofadditional stirring, 1.8 grams of sodium silicate (25% w/w aqueoussolution) was added. The pH was adjusted to 7.0 (using 5 M HCl) toproduce a final dispersion which was kept stirred at 20 C for 12 hours.An assay indicated that the dispersion comprised 7.7% active ingredient.

Example #7: Silica Coating of Bifenthrin Using Non Ionic Polymer

2.1 grams of CT AC (29% w/w aqueous solution) were added to 125 grams ofdeionized water in a 1 liter flask. 125 grams of a 20% w/w aqueousdispersion of bifenthrin (also containing 0.5% w/w CTAC) were added. Themixture was homogenized using a Polytron PT 6100 Homogenizer and theresulting dispersion transferred to a Mettler Toledo LabMax AutomaticLab Reactor.

1.8 grams of sodium silicate (25% w/w aqueous solution) were added andthe mixture was stirred for 5 minutes. The pH was adjusted to 3.0 by theaddition of 5 M HCl. The mixture was stirred for an additional 2minutes, and 3 grams of Celluol 24203 (a 3% w/w polyvinyl alcohol)added. The mixture was stirred for 5 minutes.

The process in the above paragraph (commencing with the addition of thesodium silicate) was repeated 49 times. Then, after 5 minutes ofadditional stirring, 1.8 grams of sodium silicate (25% w/w aqueoussolution) was added. The pH was adjusted to 3.0 (using 5 M HCl) toproduce a final dispersion which was kept stirred at 20 C (20° C.) for12 hours. An assay indicated that the dispersion comprised 4.2% activeingredient.

Example #8: Silica Coating of Bifenthrin Using a Copolymer

2.1 grams of CTAC (29% w/w aqueous solution) were added to 125 grams ofdeionized water in a 1 liter flask. 125 grams of a 20% w/w aqueousdispersion of bifenthrin (also containing 0.5% CTAC) were added. Themixture was homogenized using a Polytron PT 6100 Homogenizer. Anadditional 75 grams of deionized water were added and the resultingdispersion transferred to a Mettler Toledo LabMax Automatic Lab Reactor.

1.8 grams of sodium silicate (25% w/w aqueous solution) were added andthe mixture was stirred for 5 minutes. The pH was adjusted to 5.0 by theaddition of 5 M HCl. The mixture was stirred for an additional 2minutes, and 3 grams of Agrimer DA 102W (a 3% w/w aqueous suspension ofvinyl pyrrolidone/dimethylaminoethyl methacylate copolymer) added. Themixture was stirred for 5 minutes.

The process in the above paragraph (commencing with the addition of thesodium silicate) was repeated 49 times. Then, after 5 minutes ofadditional stirring, 1.8 grams of sodium silicate (25% w/w aqueoussolution) was added. The pH was adjusted to 5.0 (using 5 M HCl) toproduce a final dispersion which was kept stirred at 20 C for 12 hours.An assay indicated that the dispersion comprised 4.0% active ingredient.

Comparative Experiment A

Employing a sol-gel process of the type disclosed in U.S. Pat. No.6,303,149, a core/shell composition of bifenthrin was prepared employingan aqueous phase comprising cetyltrimethylammonium chloride and anorganic phase comprising tetraethoxysilane (TEOS) and bifenthrintechnical in an aromatic organic solvent. The composition comprised 8.4%w/w of 96% bifenthrin technical.

Biological Testing

The residual activity of the above formulations on a porous surface(cement) against German Roaches was evaluated as follows:

Poured cement tiles were produced by mixing 1 part water with 3 partsdry cement mix powder (Quikrete or Sakrete). Once thoroughly mixed, thewet cement was poured directly into the “lid” side of plastic Petridishes (100×20 mm). Enough wet cement was added to form a thin layer ofcement 5-10 mm thick. The lids were agitated slightly to flatten out thecement and to prevent it from drying unevenly. The wet dishes wereallowed to cure for 24 hours. The walls of the bottom of each Petri dishwere coated with a 50/50 mixture of mineral oil and petroleum jelly toprevent the roaches from climbing up onto the untreated plastic portionof the Petri dishes, thereby escaping the treated cement surface.

The initial compositions above were diluted with distilled water to anapplication rate of 0.5 oz/gallon. A DeVilbis hand sprayer was used tospray the tiles, with treatments being applied at a rate ca. 0.005mL/cm2. The tiles were moved into a drying hood and held for 1-2 hoursuntil completely dry. They were then used for initial (day 0) testing,or stored (at ambient humidity and at 68-75° F.) for residualevaluation.

German roaches were knocked down with carbon dioxide and transferredwith featherweight forceps directly on to the treated surface. Tenroaches were added to each treated surface and the mineral oil/petroleumjelly coated Petri dish bottom was used as a cover. The percentage ofroaches that were “knocked down” (which includes insects that weremoribund i.e, showed movement but failed to right themselves when turnedover—or dead) was recorded at various time intervals.

The formulation of Comparative Experiment A showed no activity after 24hours exposure after a 2 day residual treatment. In contrast, after a 28day residual treatment, the formulations of Examples 6, 7 and 8exhibited the following activity after 24 hour exposure:

Laver % Knockdown Example Coating After 24 Hour Exposure Control None 06 PDAC 90 7 PVA 100 8 Agrimer 100

The above results show that the compositions prepared by the method ofthis invention exhibit unexpectedly prolonged activity of cementsurfaces relative to the prior art process which also coats thebifenthrin with a silica shell.

While this invention has been shown and described with reference topreferred embodiments thereof, it will be understood by those skilled inthe art that many alternatives, modification and variations may be madehereto without departing from the spirit and scope of the invention.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference.

What is claimed is:
 1. A method for treating a surface condition in asubject, comprising topically administering onto the surface acomposition comprising an effective amount of dispersed particlescomprising solid benzoyl peroxide particulate matter encapsulated by ametal oxide coating, wherein the metal oxide coating comprises four ormore layers, wherein the outermost portion of the metal oxide coatingbeing substantially free of benzoyl peroxide; wherein, (i) the coatedparticles having leaching of less than 5% w/w, of the benzoyl peroxidein the composition until administered to the skin; (ii) the coatedparticles release an effective amount of benzoyl peroxide when thecomposition is in contact with the surface; (iii) the time for releasing50% w/w of the benzoyl peroxide being at least two-fold longer when incoated form than the time to dissolution of benzoyl peroxide particlesof the same particle size diameter when in free form under identicalconditions.
 2. The method of claim 1, wherein said surface is skin ormucosal membrane.
 3. The method of claim 1, wherein said surfacecondition is a disease or disorder selected from the group consisting ofacne, infection, inflammation, pruritus, psoriasis, seborrhea, contactdermatitis, rosacea, and a combination thereof.
 4. The method of claim1, wherein said metal oxide is selected from Silica, Titania, Alumina,Zirconia, ZnO, and mixtures thereof.
 5. The method of claim 4, whereinthe metal oxide is silica.
 6. The method of claim 1, wherein the weightratio of the metal oxide to said particulate matter is in the range of1:99 to 40:60.
 7. The method of claim 1, wherein the four or more layersof said metal oxide has a thickness of 0.1-10 micron.
 8. The method ofclaim 1, wherein the metal oxide coating comprises between 4 to 1000layers, more preferably 4 to 300 layers, more preferably 4 to 100layers.
 9. The method of claim 1, wherein the solid benzoyl peroxideparticles encapsulated by a metal oxide coating have a diameter ofbetween 0.5-100 micron.
 10. Particles comprising solid benzoyl peroxideparticulate matter encapsulated by a metal oxide coating, wherein themetal oxide coating comprises four or more layers; wherein the outermostportion of the metal oxide coating being substantially free of benzoylperoxide the coated particles having teaching of less than 5% w/w, ofthe benzoyl peroxide in the composition until administered to the skin;the coated particles release an effective amount of benzoyl peroxidewhen the composition is in contact with the surface; and the time forreleasing 50% w/w of the benzoyl peroxide being at least two-fold longerwhen in coated form than the time to dissolution of benzoyl peroxideparticles of the same particle size diameter when in free form underidentical conditions.
 11. The particles of claim 10, wherein said metaloxide coating has a thickness of 0.1-10 micron.
 12. Particles comprisingsolid benzoyl peroxide particulate matter encapsulated by a metal oxidecoating, wherein the metal oxide coating comprises four or more layers,wherein the outermost portion of the metal oxide coating beingsubstantially free of benzoyl peroxide; wherein the particles areprepared by the following steps: a) contacting in a medium consisting ofan aqueous medium, the solid benzoyl peroxide particulate matter, with afirst cationic additive being a cationic surfactant, to obtain adispersion of said benzoyl peroxide particulate matter in said aqueousmedium, said benzoyl peroxide particulate matter having positive chargeson its surface; b) adding an aqueous solution of a metal oxide salt tosaid dispersion of said benzoyl peroxide particulate matter, underconditions wherein said metal oxide salt precipitates onto the surfaceof said benzoyl peroxide particulate matter, and acidifying to therebyform a solid, water-insoluble benzoyl peroxide particulate matter thathas a metal oxide layer coated thereon; b1) contacting, in a mediumconsisting of an aqueous medium, said benzoyl peroxide particulatematter coated with a metal oxide layer of the preceding step with asurface adhering additive being one or both of (i) a second cationicadditive being a cationic polymer and (ii) a non-ionic additive, toobtain a dispersion of said coated benzoyl peroxide particulate matterhaving an adhering additive on the surface thereof in said aqueousmedium; b2) bringing the dispersion obtained in step (b1) into contactwith an aqueous solution of a metal oxide salt, under conditions whereinsaid metal oxide salt precipitates onto the surface of said coatedbenzoyl peroxide particulate matter, and acidifying to thereby form asolid, water-insoluble benzoyl peroxide particulate matter that has afurther metal oxide layer coated thereon; c) repeating steps (b1) and(b2) at least 3 more times; and d) after completion of step (c), agingthe metal oxide layer to form an aged, coated, solid, water-insolublebenzoyl peroxide particulate matter having a coating thickness in therange of 0.1-10 micron.